To make drugs from a bioprocess, the cells need to stay alive. Anyone with experience in culturing cells knows just how complicated that can get. The key challenge is avoiding apoptosis, which is programmed cell death. That’s just what professor of biomedical engineering Sakis Mantalaris, PhD, and his colleagues study at the Georgia Institute of Technology in Atlanta.

Across the bioprocessing industry, cell death can create a big problem in production. “Apoptosis has been reported to be the most important cause of death in all industrially-relevant cell lines—being responsible for 80% of cell deaths in Chinese Hamster Ovary and 90% in TB/C3 hybridoma cell cultures,” says Mantalaris.

Sakis Mantalaris, PhD [Georgia Tech]
Making the problem of apoptosis even more complicated, Mantalaris points out that many factors can cause it. As examples, he mentions a lack of nutrients, excess metabolites, hypoxia, shear stress from mixing, temperature excesses, pH, osmotic pressure, and the misfolding of proteins that causes endoplasmic-reticulum stress. That creates a wide range of factors that must be examined if cells are dying in a bioreactor.

Mantalaris adds that “a variety of approaches have been utilized to reduce apoptosis in bioprocessing.” As he notes, these include apoptosis engineering, which is a cell-line approach that targets rational gene-expression modifications towards the development of apoptosis-resistant cell lines, and traditional bioprocess engineering methods that include media design, control of bioprocess parameters, and perfusion cultures.

As Mantalaris shows, it takes a broad look at a cell line to find the source of apoptosis, when it occurs. Isolating the problem can be complicated, due to the wide range of possible causes. Nonetheless, apoptosis needs to be avoided as much as possible. Otherwise, a bioreactor batch can produce far less product than expected.